Candida albicans is one of the most frequently isolated fungal pathogens of humans. It can undergo reversible morphogenetic transitions between budding yeast, pseudohyphal, and hyphal growth forms. Its unique ability to switch from yeast to hyphal growth in response to various host and environmental signals is essential to its pathogenicity. Many hypha-specific genes encode virulence factors. Hyphal development is regulated by multiple signal transduction pathways. Among them, the cAMP-dependent protein kinase A (PKA) pathway is a major regulator of morphogenesis and virulence. Despite its importance, the molecular mechanism for how the cAMP-PKA pathway activates the hyphal transcriptional program is still not known. We find cAMP- PKA dependent down-regulation of the major repressor of hyphal morphogenesis, Nrg1, correlates with the initiation of the hyphal transcriptional program. Sustained hyphal transcription requires Hda1 being recruited to the promoters of hypha-specific genes, where it leads to changes in promoter chromatin. We propose to determine the mechanisms and regulators for cAMP-PKA dependent Nrg1 down-regulation upon hyphal induction in Aim 1. Aim 2 defines host factor(s) and C. albicans pathways for the promoter recruitment of Hda1 and its importance in invasive candidiasis. Aim 3 studies functions and regulation of Cph2. A combined approach using molecular genetics, cell biology and biochemistry will be taken in our studies. This work will provide us with a better understanding of how C. albicans integrates various signals to control growth and development, and how it survives and grows in various host environments. PUBLIC HEALTH RELEVANCE: Candida has emerged as a significant human pathogen. It causes common mucosal manifestations such as oropharyngeal thrush and vaginitis. In hospitalized patients, disseminated candidiasis is the fourth most common infection (outpacing all gram-negative species) and carries a mortality rate in excess of 30%. Development of the next generation of antifungal agents will require a further understanding of the biology of Candida.